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Type 1A Diabetes (Immune Mediated) Clinical Immunology Society

Type 1A Diabetes (Immune Mediated) Clinical Immunology Society. George S. Eisenbarth Barbara Davis Center for Childhood Diabetes Slides Chosen From Teaching Slides of: Type 1 Diabetes: Molecular, Cellular, Clinical Immunology -www.barbaradaviscenter.org.

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Type 1A Diabetes (Immune Mediated) Clinical Immunology Society

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  1. Type 1A Diabetes(Immune Mediated)Clinical Immunology Society George S. Eisenbarth Barbara Davis Center for Childhood DiabetesSlides Chosen From Teaching Slides of: Type 1 Diabetes: Molecular, Cellular, Clinical Immunology-www.barbaradaviscenter.org Made possible through an unrestricted educational grant from KRONUS.

  2. WWW.BARBARADAVISCENTER.ORG: Book: Immunology Type 1 Diabetes • Teaching slides are Powerpoint slide sets that can be downloaded. • Primer Immunology and Autoimmunity(Updated - 12/03) Stephanie C. Eisenbarth2A. Cell Therapy of Diabetes(Updated - 3/02)Jan Nygaard Jensen and Jan Jensen2B. Proprotein Processing and Pancreatic Islet Function(Updated - 3/02)John Hutton, Tina Wasmeier, Rodabe Amaria, Nicholas Bright and John Creemers2C. Stimulus-Secretion Coupling in the Pancreatic Beta-Cell (Updated - 3/02)Kirstine Juhl and John Hutton 3. Animal Models of Type 1 Diabetes: Genetics and Immunological Function(Updated - 8/02)Julie Lang and Donald Bellgrau4. The Role of T Cells in Beta Cell Damage in NOD Mice and Humans (Updated - 3/02)Katalin Kelemen5. Type 1 Diabetes Mellitus: An Inflammatory Disease Of The Islet(Updated - 12/03)Regine Bergholdt, Peter Heding, Karin Nielsen, Runa Nolsøe, Thomas Sparre, Joachim Størling, • Allan E. Karlsen, Jørn Nerup, Flemming Pociot and Thomas Mandrup-Poulsen. Steno Diabetes • Center, Gentofte, Denmark6. The Immunobiology of Pancreatic Islet Transplantation (Updated - 11/01)Marilyne Coulombe and Ronald G. Gill7. Type I Diabetes Mellitus of Man: Genetic Susceptibility and Resistance (Updated - 4/02) A. Pugliese and G. S. Eisenbarth8. Autoimmune Polyendocrine Syndromes(Updated - 10/03)J.M. Barker and G. S. Eisenbarth9. Epidemiology of Type I Diabetes(Updated - 4/02)Marian Rewers, Jill Norris and Dana Dabelea10. Humoral Autoimmunity(Updated - 9/02) L. Yu and G.S. Eisenbarth11. Prediction of Type I Diabetes: The Natural History of the Prediabetic Period(Updated - 11/03)George S. Eisenbarth12. Clinical Trials for the Prevention of Type I Diabetes(Updated - 9/03)H. Peter Chase, Anthony R. Hayward & G. S. Eisenbarth

  3. Age (years) 1986 NEJM “Stages” in Development of Type1Diabetes (?Precipitating Event) Genetic Predisposition Overt immunologic abnormalities Progressive loss insulin release Normal insulin release Overt diabetes Beta cell mass Glucose normal C-peptide present No C-peptide

  4. 350 300 250 200 150 100 50 '66 '68 '70 '72 '74 '76 '78 '80 '82 '66 '67 '68 '69 '70 '71 '72 '73 '74 '75 0 Triplets Serial Intravenous Glucose Tolerance Tests ANTIBODY POSITIVE ANTIBODY NEGATIVE * ** Peak insulin response to intravenous glucose (1+3 min) immunoreactive insulin (μU/ml) * DM Srikanta S. et al, New Engl J Med 308:322-325, 1983

  5. Stages Type IA Diabetes • I Genetic Susceptibility • II Triggering • III Active Autoimmunity • IV Progressive Metabolic Abnormalities • V Overt Diabetes • VI Insulin Dependence

  6. Monogenic:Single gene defect. APS-I: AIRE autosomal recessive XPID: Scurfy Gene X-linked Polygenic:Summation of small effects of multiple genes creating diabetes susceptibility (e.g. NOD mouse) Oligogenic:MHC+few major genes Genetic heterogeneity with different major non-MHC genes for different families (e.g. BB rat) Type 1A Diabetes BDC

  7. J. Noble HLA Human Leukocyte Antigen human MHC cell-surface proteins important in self vs. nonself distinction present peptide antigens to T cells CLASS II: DR,DQ,DP CLASS I: A,B,C

  8. J. Noble TERMINOLOGY Allele: DRB1*0401 DR4 Haplotype: DRB1*0401 DQB1*0302 DR4 DQ8 DRB1*0401 DQB1*0302 Genotype DR4 DQ8 DRB1*0301 DQB1*02(DQ2) DRB1*02 DR3 DQ2

  9. DQB1*0402  -chain Leu56 -chain Asp57 BDC BDC

  10. BDC

  11. The IDDM2 Locus IDDM2 Insulin Gene (INS) Predisposing Class I VNTR 26-63 repeats 21 alleles IDDM2 Insulin Gene (INS) Protective Class III VNTR 140-200 repeats 15 alleles VNTR = Variable Number of Tandem Repeats

  12. InheritedSusceptibility Loci LOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITES IDDM1 6p21HLA-DQ\DR IDDM211p15INS VNTR IDDM3 15q26 D15s107 IDDM411q13MDU1, ZFM1, RT6,FADD/MORT1, LRP5 IDDM56q24-27 ESR,MnSOD IDDM6 18q12-q21D18s487, D18s64, JK (Kidd locus) IDDM72q31 D2s152, IL-1,NEUROD, GALNT3 IDDM8 6q25-27 D6s264, D6s446, D6s281 IDDM9 3q21-25 D3s1303 IDDM10 10p11-q11 D10s193, D10s208, D10s588 IDDM11 14q24.3-q31 D14s67 IDDM122q33CTLA-4, CD28 IDDM13 2q34 D2s137, D2s164, IGFBP2, IGFBP5 IDDM14 ?NCBI # 3413 IDDM15 6q21 D6s283, D6s434, D6s1580 IDDM16 ? NCBI # 3415 IDDM1710q25D10s1750-D10s1773 OTHERS

  13. Autoimmune Polyendocrine Syndromes • APS-II (Autoimm Polyendocrine) • APS-I (AIRE mutation) • XPID: (Scurfy Mutation) • Anti-insulin Receptor Abs + “Lupus” • Hirata (Anti-insulin Autoantibodies) • POEMS (Plasmacytoma,..) • Thymic Tumors + Autoimmunity • Congenital Rubella + DM +Thyroid

  14. APS-SyndromesBetterle et al. Endocrine Reviews 23:327-364Neufeld and Blizzard: 1980, Pinchera, in Symposium Autoimmune Endocrine Aspects of Endocrine Disorders • APS-I:>=2 of Candidiasis, Hypopara,Addison’s • APS-II:Addison’s + Autoimmune Thyroid and/or Type 1 Diabetes • APS-III: Thyroid Autoimmune + other autoimmune [not above] • APS-IV: Two or more organ-specific autoimmune, not I,II, or III.

  15. General Paradigm • Identify Genetic Susceptibility • Detect Initial Autoantibodies • Monitor Metabolic Decompensation • Treat Overt Disease Prior to Morbidity/Mortality • Basic/Clinical Research to Allow Prevention

  16. Associated Autoimmune Illnesses

  17. Onset Infancy SiblingsAIRE gene mutated Not HLA Associated ImmunodeficiencyAsplenismMucocutaneous Candidiasis 18% Type 1 DM Older Onset Multiple Generations DR3/4 Associated No Defined Immunodeficiency 20% Type 1 DM Comparison APS-I and APS-IIAPS-IAPS-II BDC

  18. APS-I • Autoimmune Polyendocrine Syndrome Type 1 • Autosomal Recessive mutations AIRE (Autoimmune Regulator) gene • Mucocutaneous Candidiasis/Addison’s Disease/Hypoparathyroidism • 18% Type 1 Diabetes • “Transcription Factor” in Thymus BDC

  19. XPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea • Other NamesIPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linkedXLAAD: X-Linked Autoimmunity Allergic Dysregulation • Foxp3 Gene Mutation • Loss of Regulatory T LymphocytesBone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man BDC

  20. Mutations for XPID Syndrome Scurfy/Foxp3/JM2 Gene Fork Head Homology Zn Zip ORF X XLAAD-100 D XLAAD-200 Scurfy X Zn = Zinc-finger domain, Zip = Zip Motif ORF = Predicted Open Reading Frame Modified from Review by Patel, JCI, 2000

  21. Major DR/DQ Associations • Type 1 DiabetesDR3: DRB1*0301/DQA1*0501/DQB1*0201DR4: DRB1*0401/DQA1*0301/DQb1*0302 • Celiac DiseaseThe same as Type 1 DM plusDR5/DR7 = DQA1*0501/DQB1*0201 in trans • Addison’s DiseaseThe same as Type 1 DM but DRB1*0404 preference (Yu, JCEM 84:328,1999) BDC

  22. Known Initiators

  23. Mediator/Autoantigen(s)

  24. Celiac Disease • Intestinal Autoimmune Disorder • Anti-Transglutaminase (EMA) • 1/200 General Population U.S./Europe1/20 Patients with Type 1 DM1/6 Patients Type 1 DM who are DR3/DR3 • Gliadin Induction • Hypothesis: transglutaminase+gliadin

  25. Prevalence of TGA by HLA-DR amongst patients with type 1 DM, relatives of DM patients and general population Prevalence HLA-DR BDC

  26. Stages Type IA Diabetes • I Genetic Susceptibility • II Triggering • III Active Autoimmunity • IV Progressive Metabolic Abnormalities • V Overt Diabetes • VI Insulin Dependence

  27. Environment • Congenital Rubella • Controversy re Enteroviruses/ other virus • Controversy re bovine milk • Hygiene Hypothesis • 2 JAMA papers re early cereal

  28. BabyDiab and DAISY Age introduction gluten (Ziegler) or cereal (Norris) greatly increases development of anti-islet autoantibodies in infants followed from birth.

  29. Stages Type IA Diabetes • I Genetic Susceptibility • II Triggering • III Active Autoimmunity • IV Progressive Metabolic Abnormalities • V Overt Diabetes • VI Insulin Dependence

  30. Insulin Autoantibodies: A Chain L13 Receptor Binding Region

  31. Experimental Autoimmune Diabetes B:9-23 Peptide ----- Insulin Autoantibodies B:9-23 Peptide + Poly-IC ------ Insulitis B:9-23 Peptide + Poly-IC + B7.1 Islet -- Diabetes Moriyama et al. PNAS 99: 5539-5544, 2002

  32. Difference of Amino acid sequence between preproinsulin 1 and 2 Leader 1: MALLYHFLPL LALLALWEPKPTQA 6 Leader 2: MALWMRFLPL LALLFLWESHPTQA B:9-23 B Chain 1: FVKQHLCGPHLVEALYLVCGERGFFYTPKS 2 B Chain 2: FVKQHLCGSHLVEALYLVCGERGFFYTPMS C-Peptide 1: EVEDPQVEQLELGGSPGDLQTLALEVARQ 5 C-Peptide 2: EVEDPQVAQLELGGGPGAGDLQTLALEVAQQ A Chain 1: GIVDQCCTSI CSLYQLENYC N 0 A Chain 2: GIVDQCCTSI CSLYQLENYC N

  33. PNAS 2003,18:10376

  34. Diabetes Autoimmunity Study in the Young General population cohort Sibling/offspring cohort screened = 21,713 enrolled = 293 high risk 72 429 moderate risk 220 347 average - low risk 401 1,069 All 693 relatives 1,491 1,007

  35. HLA-defined IDDM risk groupsDenver population, n=9,338

  36. Autoantibodies • Insulin • Glutamic Acid Decarboxylase • ICA512 (IA-2)

  37. IAA assay

  38. 10000 1000 Anti-insulin autoantibodies (nU/ml) 100 10 1 5 10 15 20 25 30 35 Age (years) Insulin Autoantibodies Versus Age of Diabetes Onset Diabetes Care 11:736-739, 1988

  39. The Levels of mIAA in Prediabetic Children DM DM DM DM DM Yu et al. PNAS: 97:1701-1706, 2,000 BDC

  40. Progression to Diabetes vs Number of Autoantibodies (GAD, ICA512, Insulin) Percent not Diabetic Years of Follow-up 3 Ab n = 41 17 8 1 2 Abs n = 44 27 15 4 2 1 1 Abs n = 93 23 14 10 6 4

  41. Stages Type IA Diabetes • I Genetic Susceptibility • II Triggering • III Active Autoimmunity • IV Progressive Metabolic Abnormalities • V Overt Diabetes • VI Insulin Dependence

  42. We can now predict type 1 diabetes. We cannot now prevent type 1 diabetes.

  43. What are we missing? Assay for Pathogenic T cells. ? TETRAMER ? ELISPOT

  44. % tetramer+ CD8+ cells % tetramer+ CD8+ cells Age (weeks) Age (weeks) Female NOD Mice Peripheral Blood Kd NRP-V7 Peptide (KYNKANVFL) Tetramer Analysis Avidin Kd Kd IGRP-2nd Beta Cell Specific Ag Kd Diabetes No Diabetes Trudeau,Santamaria,Tan: JCI 2003

  45. Multiple Trials New Onset Planned/ Underway • Anti-CD3 Monoclonal • Anti-IL2 Receptor + MMF • Altered Peptide Ligand B:9-23 insulin • HSP 60, p277 Peptide (LADA Pts) • GAD65 (LADA patients)

  46. Changes from Study Entry to 12 Months in the Total C-Peptide Response to Mixed-Meal Tolerance Testing Monoclonal-Antibody Group Control Group Total Area under the C-Peptide Response Curve (nmol/l/4 hr) Total Area under the C-Peptide Response Curve (nmol/l/4 hr) Herold K. et al., N Engl J Med 2002; 346:1692-8.

  47. Large NIH Prevention Initiatives • Immune Tolerance Network • DPT-1 ===> TrialNet • Autoimmunity Centers Excellence • Autoimmunity Prevention Centers Rewers-BDC

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